The term "complement" refers to a complex group of proteins in body fluids that, working together with antibodies or other factors, play an important role as mediators of immune, allergic, immunochemical and/or immunopathological reactions. The reactions in which complement participates take place in blood serum or in other body fluids, and hence are considered to be humoral reactions.
With regard to human blood, there are at present more than 11 proteins in the complement system. These complement proteins are designated by the letter C and by number: C1, C2, C3 and so on up to C9. The complement protein C1 is actually an assembly of subunits designated C1q, C1r and C1s. The numbers assigned to the complement proteins reflect the sequence in which they become active, with the exception of complement protein C4, which reacts after C1 and before C2. The numerical assignments for the proteins in the complement system were made before the reaction sequence was fully understood. A more detailed discussion of the complement system and its role in the body processes can be found in, for example, Bull. World Health Org., 39, 935-938 (1968); Ann. Rev. Medicine, 19, 1-24 (1968); The John Hopkins Med. J., 128, 57-74 (1971); Harvey Lectures, 66, 75-104 (1972); The New England Journal of Medicine, 287, 452-454; 489-495; 545-549; 592-596; 642-646 (1972); Scientific American, 229, (No. 5), 54-66 (1973); Federation Proceedings, 32, 134-137 (1973); Medical World News, Oct. 11, 1974, pp. 53-66; J. Allergy Clin. Immunol., 53, 298-302 (1974); Cold Spring Harbor Conf. Cell Prolifieration 2/Proteases Biol. Control/229-241 (1975); Ann. Review of Biochemistry, 44, 697 (1975); Complement in Clinical Medicine, Disease-a-month, (1975); Complement, Scope, December 1975; Annals of Internal Medicine, 84, 580-593 (1976); "Complement: Mechanisms and Functions", Prentice-Hall, Englewood Cliffs, N.J. (1976); Essays Med. Biochem., 2, 1-35 (1976); Hospital Practice, 12, 33-43 (1977); Perturbation of Complement in Disease, Chap. 15 in Biological Amplification Systems in Immunology (Ed. Day and Good), Plenum, New York and London (1977); Am. J. Clin. Pathology, 68, 647-659 (1977).
The complement system can be considered to consist of three sub-systems: (1) a recognition unit (C1q) which enables it to combine with antibody molecules that have detected a foreign invader; (2) an activation unit (C1r, C1s, C2, C4, C3) which prepares a site on the neighboring membrane; and (3) an attack unit (C5, C6, C7, C8 and C9) which creates a "hole" in the membrane. The membrane attack unit is non-specific; it destroys invaders only because it is generated in their neighborhood. In order to minimize damage to the host's own cells, its activity must be limited in time. This limitation is accomplished partly by the spontaneous decay of activated complement and partly by interference by inhibitors and destructive enzymes. The control of complement, however, is not perfect, and there are times when damage is done to the host's cells. Immunity is, therefore, a double-edged sword.
Activation of the complement system also accelerates blood clotting. This action comes about by way of the complement-mediated release of a clotting factor from platelets. The biologically active complement fragments and complexes can become involved in reactions that damage the host's cells, and these pathogenic reactions can result in the development of immune-complex diseases. For example, in some forms of nephritis, complement damages the basal membrane of the kidney, resulting in the escape of protein from the blood into the urine. The disease disseminated lupus erythematosus belongs in this category; its symptoms include nephritis, visceral lesions and skin eruptions. The treatment of diphtheria or tetanus with the injection of large amounts of antitoxin sometimes results in serum sickness, an immune-complex disease. Rheumatoid arthritis also involves immune complexes. Like disseminated lupus erythematosus, it is an autoimmune disease in which the disease symptoms are caused by pathological effects of the immune system in the host's tissues. In summary, the complement system has been shown to be involved with inflammation, coagulation, fibrinolysis, antibody-antigen reactions and other metabolic processes.
In the presence of antibody-antigen complexes the complement proteins are involved in a series of reactions which may lead to irreversible membrane damage if they occur in the vicinity of biological membranes. Thus, while complement constitutes a part of the body's defense mechanism against infection it also results in inflammation and tissue damage in the immunopathological process. The nature of certain of the complement proteins, suggestions regarding the mode of complement binding to biological membranes and the manner in which complement effects membrane damage are discussed in Annual Review in Biochemistry, 38, 389 (1969); Journal of Immunology, 119, 1-8, 1195, 1358-1364, 1482 (1977).
A variety of substances have been disclosed as inhibiting the complement system, i.e., as complement inhibitors. For example, the compounds 3,3'-ureylenebis[6-(2-amino-8-hydroxy-6-sulfo-1-naphthylazo)benzenesulfoni c acid], tetrasodium salt (chlorazol fast pink), heparin and a sulphated dextran have been reported to have an anticomplementary effect, British Journal of Experimental Pathology, 33, 327-339 (1952). German Pat. No. 2,254,893 or South African Pat. No. 727,923 discloses certain 1-(diphenylmethyl)-4-(3-phenylallyl)piperazines useful as complement inhibitors. Other chemical compounds having complement inhibiting activity are disclosed in, for example, Journal of Medicinal Chemistry, 12, 415-419; 902-905; 1049-1052; 1053-1056 (1969); Canadian Journal of Biochemistry, 47, 547-552 (1969); The Journal of Immunology, 104, 279-288 (1970); The Journal of Immunology, 106, 241-245 (1971); The Journal of Immunology, 111, 1061-1066 (1973); Biochim. Biophys. Acta, 317, 539-548 (1973); Life Sciences, 13, 351-362 (1973); Journal of Immunology, 113, 584 (1974); Immunology, 26, 819-829 (1974); Journal of Medicinal Chemistry, 17, 1160-1167 (1974); Biochim. Biophys. Res. Comm., 67, 225-263 (1975); Ann. N. Y. Acad. Sci., 256, 441-450 (1975); Journal of Medicinal Chemistry, 19, 634-639, 1079 (1976); Journal of Immunology, 118, 466 (1977); Arch. Int. Pharmacodyn., 226, 281-285 (1977); Biochem. Pharmacol. 26, 325-329 (1977); Journal Pharm. Sci., 66, 1367-1377 (1977); Chem. Pharm. Bull., 25, 1202-1208 (1977); Biochim. Biophys. Acta, 484, 417-422 (1977) and Journal Clin. Microbiology, 5, 278-284 (1977).
It has been reported that the known complement inhibitors epsilon-amiocaproic acid and tranexamic acid have been used with success in the treatment of hereditary angioneurotic edema, a disease state resulting from an inherited deficiency or lack of function of the serum inhibitor of the activated first component of complement (C1 inhibitor), The New England Journal of Medicine, 286, 808-812 (1972), 287, 452-454 (1972); Ann. Intern. Med., 84, 580-593 (1976); J. Allergy and Clin. Immunology, 60, 38-40 (1977).
It has also been reported that the drug pentosanpolysulfoester has an anticomplementary activity on human serum, both in vitro and in vivo, as judged by the reduction in total hemolytic complement activity; Pathologie Biologie, 25, 33-36, 25 (2), 105-108, 25 (3), 179-184 (1977).
It is known that the compound Suramin is moderately active as a complement inhibitor, and possesses the structure: ##STR1##
It now has been discovered that certain modifications of this structure provide compounds with enhanced inhibitory activity. This invention is based on such modifications.
The following publications, pertaining to the chemistry of Suramin, are related to the preparation of the novel compounds of this invention:
Bayer & Co., D.R.P. 278,122, June 22, 1913 [C.A. 9, 1096(1915)] PA0 Bayer & Co., D.R.P. 288,272, Jan. 23, 1914 [C.A. 10, 2279(1916)] PA0 Bayer & Co., D.R.P. 288,273, Feb. 21, 1914 [C.A. 10, 2279(1916)] PA0 Frdl. 12, 185-186, 191-195 (1914-1916) PA0 Danish Pat. No. 20,743 (1915) PA0 Austrian Pat. No. 72,298 (1916) PA0 Austrian Pat. No. 72,303 (1916) PA0 U.S. Pat. No. 1,218,654 (1917) PA0 U.S. Pat. No. 1,218,655 (1917) PA0 Austrian Pat. No. 73,381 (1917) PA0 U.S. Pat. No. 1,308,071 (1919) PA0 E. Fourneau, J. Trefouel, Mme. J. Trefouel and J. Vallee, Acad. Sci. Comp. Rend., 178, 675-676 (1924) PA0 E. Fourneau, F. Trefouel and J. Vallee, Ann. de L'Institut Pasteur, 38 (2), 81-114 (1924) PA0 B. Heymann, Zeitschrift Ang. Chem., 37, 585-589 (1924) PA0 British Pat. No. 224,849 (1925) PA0 U.S. Pat. No. 1,606,624 (1926) PA0 J. E. R. McDonagh, Brit. Med. J., 693-696 (1926) [Chem. Zentralblatt, 1769-1770 (1926 II)] PA0 W. Roehl, Arch. Schiff. Trop. Hyg., 30 (1), 103-111 (1926) PA0 Poulenc Freres, D.R.P. 427,857, Apr. 20, 1926 [Frdl. 15, 1434-1436 (1928)] PA0 I. E. Balaban and H. King, J. Chem. Soc., 3068-3097 (1927) PA0 H. Bauer and J. Becker, Arb. Staatsinst. Exptl. Therap., 16 pp. (1928) PA0 U.S. Pat. No. 1,968,820 (1934) PA0 O. Yu. Magidson, O. S. Madaeva and M. V. Rubtzov, Khim. Farm. Prom., 2, 89-94 L (1935) [C.A., 30, 4492 (1936)] PA0 U.S. Pat. No. 2,126,180 (1938) PA0 P. Pratsi and L. Raffa, Farmaco Sci e Tec (Pavia), 1, 21-34 (1946) PA0 A. Spinks, Biochem. J., 42, 109-116 (1948) PA0 E. D. Wills and A. Wormall, Biochem. J., 47, 158-170 (1950) PA0 German Pat. No. 890,952 (1953) [C. A. 52, 14693 (1958)] PA0 A. Adams, J. N. Ashley and H. Bader, J. Chem. Soc., 3739-3744 (1956) [C. A. 51, 4375i] PA0 B. Stuber and K. Lang, Arch. Exptl. Path. Pharmacol., 154, 41-49 (1930) [C. A. 25, 3067(1931)] PA0 F. Klopstock, Zeitschrift fur Immunitatsforschung und experimentalle Therapie, 75, 348-354 (1932) PA0 H. J. Schmid, Schweiz. Med. Woch., 96, 1267-1269 (1966) PA0 K. Lauenstein, Bayer-Symposium I, 25-30 (1969) PA0 J. S. C. Fong and R. A. Good, Clin. Exp. Immunol., 10, 127-138 (1972) PA0 V. Eisen and C. Loveday, Br. J. Pharmac., 49, 678-687 (1973) PA0 D. Brackertz and F. Keuppers, Allergol. Et Immunopath., 11, 163-168 (1974) PA0 E. Raepple, H-U. Hill and M. Loos, Immunochemistry, 13 (3), 251-255 (1976)
Publications related to the biological use of Sumarin compounds for the purpose of inhibiting the complement system, including humans, as determined by the in vivo and in vitro testing of the blood serum of warm-blooded animals are: